Genetic risk factors in the development of hyperhomocysteinemia

Abstract

Homocysteine (HCY) is a serum-containing amino acid synthesized by its demethylation in a multi-stage process during metabolism of methionine, which is essential amino acid for humans. Through ATP, methionine is alkylated to S-adenosylmethionine (SAM). Subsequently, with the formation of S-adenosylhomocysteine (SAH), cytosine-5-methyltransferase catalyzes processes for the transfer of methyl residues from S-adenosylmethionine to cytosine residues in DNA. The following enzyme hydrolases S-adenosylhomocysteine, with the formation of homocysteine as illustrated in Fig. 8.1. S-adenosylmethionine tends to be the principal source of methyl groups for protein synthesis, purine or pyrimidine bases, nucleic acids, phospholipids, and other biologically active substances [1, 2]. The normal range of plasma homocysteine level is 5-15 μmol/L. Hyperhomocysteinemia is defined as a plasma homocysteine level >15 μmol/L and is classified as moderate (15-30 μmol/L), intermediate (30-100 μmol/L), or severe (>100 μmol/L) [3]. Hyperhomocysteinemia were first described by Carson and Neill in 1962 which is basically due to abnormal homocysteine metabolism [4]. The clinical manifestations associated with this inborn error of metabolism are mental retardation, lens dislocation, skeletal abnormalities, and early thrombotic events [5]. In 1969, it was proposed by McCully that this pathology can also be concluded as a vascular risk factor on the basis of autopsy evidence found in two children with hyperhomocysteinemia and homocystinuria with widespread arteriosclerotic changes [6]. This hypothesis was supported by successive studies [3, 7] which correlated hyperhomocysteinemia to other pathologies such as peripheral vascular, cerebrovascular, and coronary artery disease (CAD). Elevated levels of plasma homocysteine have also been shown to be concomitant with other common complications associated with aging, such as cognitive impairment, dementia, depression, osteoporotic fractures, and functional decline. It has been recently revealed in various literatures that the frequency of hyperhomocysteinemia in the overall population is between 5% and 10% [8]. However, in elderly population (older than 65 years), the rate may be noted as high as 30% according to the Framingham Study [9]. Diet supplementation with folic acid resulted in significant decline in the prevalence of the disease in United States since the beginning of 1996. Information fetched from the Framingham Offspring Study cohort showed that folate fortification has reduced the prevalence of hyperhomocysteinemia by approximately 50% [10].